As the most prevalent group of psychiatric diseases, anxiety disorders are chronic and disabling conditions that impose enormous costs on individuals and society. Anxiety disorders have complex polygenic etiologies with poorly understood underlying brain circuitries. Structures in the amygdala such as the basolateral complex are widely implicated in anxiety, but additional regions include insula cortex, medial prefrontal cortex, bed nucleus of stria terminalis, and hippocampus. Among several candidate genes, NMDA receptors (NMDARs), and GluN2B subunits in particular have been associated with anxiety. However, there is no clear picture of unique or converging molecular mechanisms that underlie these disorders. The lack of a mechanistic understanding precludes the identification of novel therapeutic targets and development of useful mouse models. These factors contribute to languishing efforts to develop drugs for pathological anxiety. This proposal seeks to test a novel molecular pathway that regulates anxiety in rodents, and test whether manipulations of this pathway can be anxiolytic. The hypothesis being tested is that Amyloid Precursor Protein Intracellular Domain Associated-1 (AIDA-1) regulates anxiety-related behaviors by controlling NMDAR function in ventral hippocampus (VH). AIDA-1 is a synaptic protein that controls GluN2B subunit function and NMDAR- dependent plasticity in the hippocampus. Preliminary findings indicate that AIDA preferentially regulates GluN2B function in VH. Behavioral testing reveals that AIDA-1 forebrain knockout mice (AIDA-1 cKO) only display reduced anxiety, and not the deficits in spatial and episodic memory expected from deficits in NMDAR function and hippocampal synaptic plasticity. Selective AIDA-1 knockdown in VH, but not in amygdala, recapitulate the reduced anxiety phenotype observed in AIDA-1 cKO mice. Our data support longstanding evidence of VH function in emotionality. The proposed studies will provide insight into AIDA-1 and NMDAR biology, and into functional differences present along the dorso-ventral axis of the hippocampus. Importantly, these experiments will provide insights into anxiety disorders, and may identify novel therapeutic targets for their treatment.